Amino arsenicals and process for preparing same



Patented Feb. 3, 1948 UNITED STATES PATENT OFFICE AMNO ARSENICALS AND PROCESS FOR PREPARING SAME Clifl Struthers Hamilton, Lincoln, Nebr., assignor to Parke, Davis & Company, Detroit, Mich., a

corporation of Michigan No Drawing. Application June 19, 1943,

Serial No. 491,563

The invention relates to new amino arsenicals.

is attached to the pyridine nucleus at one of the 2 and 4 positions and where A and B, and also X and Y, are attached to any of the available carbon atoms of the benzene and pyridine ring systems respectively. B represents a member of the class hydrogen, hydroxyl, hydroxyalkoxyl and middle halogens (chlorine and bromine). X and Y are members of the class hydrogen, nitro (NO2), amino and its acid addition salt groups NH2.HA' where A is the anion of an acid having a dissociation constant of about or more, such as hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid, tartaric acid, etc.

A is an arsenical grouping of the class, ASO3H2, AsOsI-IM, --ASO3M2, As0, --As(OI-I)2, --As(Hal)z, -AsS and -AS(SR)2 where M is a basic salt-forming group such as alkali metal, ammonium or substituted ammonium,

where Hal represents a halogen of the class chlorine, bromine and iodine, where Rrepresents an alkyl radical directly attached by a methylene linkage to the sulfur atom of --SR and containing or not the group CONH--, said radical being substituted by one of COOH and -COOM and substituted or not by one or more of -NH2 and --NH2.HA' whenever R. contains COOH, but substituted or not by one or more of :-NI-I2 only when R contains COOM, M and A being as already defined.

Although the group NH can be attached to the pyridine nucleus at either the 2 or 4 position, I prefer to attach the group at the 2 position, because of the ease of carrying out the reaction.

The compounds may be prepared by either o 15 Claims. (Cl. 260271) two methods. In the first method a chloroor bromopyridine, which may or may not be further substituted, is reacted with a substituted or unsubstituted aminobenzenearsonic acid under acid conditions as described in the pending application of Clarence Kenneth Banks, Serial No. 464,250, filed November 2, 1942.

The reaction may be illustrated graphically as follows:

where the element chlorine (or bromine) is attached to the pyridine nucleus at the two or four position. It is quite important that the hydrogen ion concentration be controlled so as to maintain a definite acidity, otherwise the yields are markedly reduced and in some cases none of the desired product is formed.

The second method consists of reacting the same type of pyridine compound as reacted in the first method and of the structure :l -OKBr) where X and Y are as previously defined and the chlorine (or bromine) is in the 2 or 4 position and the hydrogens occupy the remaining open positions at ring carbon atoms, with a substituted aniline of the structure,

where B represents groups previously described and C is an amino group, m'tro group, aoylamino group or other group which may be converted by hydrolysis or reduction to an amino group, the group C being in the meta or para position to the amino group of the above formula. The compound obtainedhas the formula and is then hydrolyzed or reduced. if necessary, 7 I

to convert C to an amino group and this product is diazotized and coupled with sodium arsenite according to the general methods of the Bart reaction, or similar known method for substituting an arsonic acid grouping for a primary amino group. If the group C of the reactant Example 1 2-chloro-5-nitropyridine (5 g.) and p-arsanilic acid (5.6 g.) are refluxed in 40 m1. of 0.875 N hydrochloric acid and 240 ml. of water for about 40*hours. The white solid "which steam distills up finto the condenser-is repeatedly scraped back into the reaction flask. After the condensate 'no {longer appears in the condenser, the refluxing is continued for another hours. The solution is "cooled and the crystallized solid filtered ofi, extracted with 100 ml. of hot water-and recrystallized from acetic acid. The product is a yellow, crystalline substance, not melting at 250 C. The --yield is 55% of the theoretical amount. The product analyzes for 22.08% arsenic; theory requires 22.09%. The product is I N O 2 2-(4'-arsonoanilino)-5-nitropyridinc pounds or intermediates for such compounds can she made. The following eompounds :arle examples of compounds whose preparation by the same or similar procedure will be apparent to those skilled in the art.

2- (3'-arsonoanilino)-5-nitropyridine 2-(2-arsonoanilino)-5-nitropyridi1ie N W. N

2-(4-arsonoanilino) pyridine AsOsHa -arso11o-2' hydroiiyanlliuo) -5-nitropyrid.ine

OCHiCHz OzN- V SOaHr AsOaHQ 2-(6-arsono-2'-hydroxyanilino) pyridine Example 2 m-Phenylenediamine (21.6 g.) anhydrous .sodium acetate (16.4 g.) and 2-chloro-5-nitropyridine (15.8 g.) are refluxed in 500 .ml. of ethyl alcohol for five hours. After charcoaling,

diluting with water and cooling, 2-(3'-am;ino-

anilino) -5-nitropyridine separates as a darlg yel 5; low product, M. P. 17830: This: compoundis, dissolved in hot water (560 ml), hydrochloric acid (40 ml.) added and, after'cooling, is diazotized with sodium nitrite at 5-10 C. The diazonium solution is coupled with a solution of' sodiumarsenite (1.5 equivalents) at C. and after:

warming slowly is filtered, the filtrate-i made acid.

to litmus paper, charcoaled and again filtered. The resulting solution is acidifieclto Congo red paper.

The product is AS O 311'? 2-(3-arson0anilino)-5-nitropyridine If p-phenylene diamine and 2-chl'or0-5-nitropyridine are used, the product i V N sOs. l

2-(4-arsonoanilino)-5-nitropyridine and if p-phenylenediamine and 4-chloro-3-nitropyridine are used, the product is rIXSOeH:

4-(4-arsonoani1ino)-3-nitropyridine Example 3 2- (4-ars0noani1ino) -5-nitropyridine (4. g.) is dissolved in water with sodium hydroxide to give a neutral to slightly basic solution and reduced at room temperature using Raney nickel catalyst and molecular hydrogen at 40 pounds pressure. After removing the catalyst, the product is isolated by acidifying the solution with dilute hy drochloric acid. It is a White, crystalline product, turning lavender when exposed to air. On heating it melts with decomposition at about 240 C. Arsenic analysis shows 24.00%, while the.

theory requires 24.23 It is NGASOQHA 2-(irarsonoanilino) fi-aminopyridine Not only can the catalytic methodsofireduce tion be used, but other common reducing agents such as ferrous hydroxide and reduced iron, as are known to one skilled'in the art, give the same product. It is also obvious that other nitro substituted compounds, for example those which may be obtained by the methods demonstrated in Examples 1 and 2, will yield the corresponding amino substituted derivatives upon reduction,

Example 4 2-'(4'-ars0n0a.ni1in0) -5 -aminopyridine (21 g.) is dissolved in. 800 ml. of 5% hydrochloric acid, one gram of potassium iodide added and:sulinr 6; dioxidescaspassedthroushtnesolution untilrrer action ceases. Theexcess; sulfur. dioxide is'boiled out: and suilicienirammonia; added to give anew- The: product pre-. cipitates as a nearlyw-hite:powdensinteringratr tralgreactionto litmus paper.

122 C. and decomposing;at 132 C. Arsenic-analysis shows 25.15%, the theory, requires-2.5.35%. The product is 2e(4fi'arsinosoanllinc)#c eminopyridima monohydrate By using any 01 the arsenic acids made avails able, by; exercising the techniques described; in Examples 1,2. and 3., inplace of 2. (4.'-arsono.- anilino) -5.-aminopyridine, the. corresponding arsine. oxides. may. be. prepared.

Example 5 One-tenth mole ofv 5+amino-2-(4-arsinosoanilino) pyridine is suspendedin water and 0.2 mole of thioglycollic acid and- 0.2 mole of sodium hydroxide added. A-.clearsolution-is formed, which; is filtered and carefully. acidified; Theproduct is filtered oil and washed repeatedly to remove any unreacted' materials. It-is OAMSCHMOOHM 5-amino-2 bi -di-tcarboxymethylenethio) arsinosoanilino] pyridine This: product. may. be, dissolved in dilute sodium hydroxide and' the crystalline sodium salt thrown out by the addition of alcohol and ether. It has the formula l. N NOAs SOHzCOONiih I NH, i

and their HAf acidadditionr salts, where A represents one of the pentavalent arsenic groups AsOzfiM or ---ASO3M2, can" easily be reduced in t-he resencev of middle halogen acids:

to give the corresponding trivalent arsenical compounds and" their hydrohalides where A is one of ASC'12,ASBI'2 and. (by simple neutralization) AsO and'--As(OH)2. In this way there are? obtained: the valuable arsenicals of the for-.

and their HA acid addition salts, where A-is a.

member of the class --As(OH) 2, the group A being the anion of an acid having a dissociation constant of at least about 19- and being Cl whenever A is -AsCl2 andBr whenever A is AsBrz.

What I claim as my invention is: 1. A compound of the formula and. M is a basic salt-forming group; 2. A compound of the formula where X is a member of the class consisting of H, NOz, NHz and NH2.HA', A being the anion of an acid having a dissociation constant of at least A is an arsenical grouping of the class consisting of AsOsHa, -ASQ3HM,

and As(SCI-IzCOOM) 2, and M is a basic salt;-

fo'rming group.

' v 3. A compound of the formula and its HA acid addition salts, where A is the A anion of an acid having a dissociation constant of at least 10*, A is an arsenical grouping of the class consisting of AsOcHz, AsOzI-IM, -AsO3M2, --AsO, As (OH) 2, -As(SCH2COOH) 2 andj- -As(SCI-I2COOM)z, and M is a basic salt forming group.

4. A compound of the formula and its HA acid addition salts, where A is the anion of an acid having a dissociation constant of at least 10 and M is a member of the class consisting of hydrogen and a basic salt-forming group.

5. A compound of the formula -scmo o OM) iris-QNHONH: V

where: M is a member of the classconsisting of hydrogen and a basic salt-forming group.

6. A compound of the formula f I 1 HzOaAs-ONH-GNH:

. V r N and its HA acid addition salts, where A is the anion of an acid having a dissociation at least 10 7. A compound of the formula constant'of 8 A compound of the formula v OASONHONEH N o, a

and its HA acid addition salts, where A is the anion of an acid having a dissociation constant of at least 10- 7 I 9. A compound of the formula 10. A compound of the formula where X is'a member of the class consisting of H, --NO2, NH2 and NH2.HA', and A is the anion of an acid having a dissociation constant of at least 10- e e 11. Process for the preparation of pyridyla-' minobenzene arsenicals which comprises reacting in acidic aqueous medium, a pyridine compound of the formula V a r Hal X N V with an aminoben'zenearsonic acid of formula V HiOiAS where B is a member of the class consisting of H, OH, O-alkylene-OH, Cl and Br, H81

is a member of the class consisting of Cl and Br attached to one of the positions 2 and 4 of the pyridine nucleus of said pyridine compound and X is a member of the class consisting of H' and NOz.

12. Process for the preparation of pyridylaminobenzene arseni-cals which comprises reacting in acidic aqueous medium, a pyridine compounds 7 A of the formula Hal V p p V with an aminobenzene arsenic acid of formula where Hal is a member of the class consisting of Cl and Br attached to one of the positions2 and 4 of the pyridine nucleus of said pyridine compound, and X is'a member of the class consisting of I-! and-NOz. r r

13. Process for the preparation pf pyridylaminobenzene arsenicals which comprises reacting in acidic aqueous medium, a pyridine compound of the formula V-NO2 with an aminobenzene arsenic acid of formula where Hal is a member of the class consisting of '1C1 and Br attached to one of the positions 2 and 40f the V V pyridine nucleus of said pyr i e compound. 7

9 14. Process for the preparation of pyridylaminobenzene arsenicals which comprises reacting in acidic aqueous medium, a pyridine compound of the formula Halwith an aminobenzene arsonic acid oi. formula HiOiASONE:

where Hal is a member of the class consisting of 15 in acidic aqueous medium, a pyridine compound of the formula with an aminobenzene arsonic acid of formula moms-4113,

CLIFF STRUTHERS HAMILTON.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Name Date Freidheim Nov. 16, 1943 Number 

